Ethylnitrosourea induces neural progenitor cell apoptosis after S-phase accumulation in a p53-dependent manner

Neurobiol Dis. 2005 Feb;18(1):218-25. doi: 10.1016/j.nbd.2004.09.015.

Abstract

Neural progenitor cells populate the ventricular zone of the fetal central nervous system. In this study, immediately after the administration of ethylnitrosourea (ENU), an alkylating agent, an accumulation of neural progenitor cells in the S phase was observed. This event was caused by the inhibition or arrest of DNA replication rather than acceleration of the G1/S transition. Soon after this accumulation reached its peak, the number of cells in the G2/M phase decreased and the apoptotic cell count increased. In p53-deficient mice, both ENU-induced apoptosis and S-phase accumulation were almost completely abrogated. These findings indicate that ENU inhibits or arrests DNA replication in neural progenitor cells during the S phase and then evokes apoptosis before the cells enter the G2 phase. Furthermore, these data also demonstrate that both ENU-induced apoptosis and cell cycle perturbation in the S phase require p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Brain / cytology
  • Brain / drug effects
  • Brain / embryology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Carcinogens / pharmacology*
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • DNA Replication / drug effects
  • DNA Replication / physiology
  • Disease Models, Animal
  • Ethylnitrosourea / pharmacology*
  • Female
  • G2 Phase / drug effects
  • G2 Phase / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Neurons / drug effects
  • Neurons / metabolism
  • Rats
  • Rats, Inbred F344
  • S Phase / drug effects
  • S Phase / physiology
  • Stem Cells / drug effects*
  • Stem Cells / metabolism
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Carcinogens
  • Tumor Suppressor Protein p53
  • Ethylnitrosourea